Various functions of human beings and other organisms grow within a limited range and the variation thereof has a regular periodicity. This is called biorhythms in general. The most fundamental biorhythm is a variation having a cycle of approximately one day and is called a circadian rhythm. The circadian rhythm is an endogenous rhythm operated by “program which counts the time autonomously” inherent to the living body itself, or the so-called endogenous clock function (which is also called a biological clock or body clock) and is different from an exogenous rhythm which is entirely dependent upon physical changes surrounding the living body (such as day and night, rotation of the earth, and changes in temperature, humidity and atmospheric pressure).
These rhythms can be discriminated by checking whether the rhythm still exists when outside factors are removed as completely as possible. In an environment where periodicity has no effect, such as in a laboratory which is isolated from the outside, the human body exhibits a cycle of longer than 24 hours. Such a cycle is called a free-run cycle and is believed to be an endogenous cycle, or body clock (the free-run cycle of a human being is 24.2 hours).
A body clock with a free-run cycle that is not 24 hours, synchronizes with outside physical changes, and usually agrees with the changes in day and night, to give a 24-hour cycle. This is called rhythm synchronization and the resulting rhythm in 24-hour cycles is called infradian rhythm. However, synchronization of rhythm means not only a mere agreement of 24 hour cycles but also an establishment of a time relation of 1:1 between the specific phase of the body clock and that of the exogenous environmental rhythm, the latter being more important. For example, the initiation time of activity periods of animals is determined by the body clock. In diurnal animals, as a result of rhythm synchronization, there is an agreement between sunrise which is a specific phase of the environmental rhythm and activity periods which are established by specific phases of the body clock.
Infradian rhythm appears not only in sleep habits and diet, but also in body temperature, blood pressure, heart rate and internal secretion, and in the treatment and prevention of diseases of the heart and blood vessel systems, it is believed to be important to understand the infradian rhythms of the autonomic nervous system, endocrine system, hemodynamics, etc. and to maintain them normally. In modern society where artificial and irregular life cycles are imposed by shift work, travel by air over long distances, aging society, diversification of life styles, etc. is becoming usual, there has been an unexpected increase in various diseases caused by biorhythm disorders, such as infradian rhythm sleep disorder and there has been a brisk demand for an effective countermeasure for treating these diseases.
In an asynchronous syndrome (jet lag) due to abnormality of infradian rhythm, insomnia at night or sleeping in the daytime may result, moreover, headache, tinnitus, palpitation, nausea, gastralgia and diarrhea may also result, causing a decrease in judgment and concentration. In addition, delayed sleep phase syndrome (DSPS) is the highest at the onset of puberty (Diagnostic Classification Steering Committee, Thorpy, M. J.: International Classification of Sleep Disorders: Diagnostic and Coding Manual. American Sleep Disorders Association, Rochester, 1990). An infradian rhythm sleep disorder in young people makes their adaptation to society difficult and their development is inhibited (Kajimura, N., et al.: Nippon Rinsho, Vol. 56, No. 2, page 404, 1998).
As a method for adjusting the abnormality of infradian rhythm causing such symptoms, there are a psychotherapeutic approach, non-drug therapy and drug therapy. As a non-drug therapy, irradiation with bright light is available, and at present, it is positively used for the treatment of seasonal emotional disorder and infradian rhythm sleep disorder. Hypnotics which are used for drug therapy are roughly classified as barbiturate type, non-barbiturate type and benzodian type. Although the drugs of a barbiturate type have a strong sleep-inducing action, they are also toxic, and their tendency to suppress respiration and circulation becomes stronger as the concentration thereof in the blood is increased, so that their use must be carefully controlled.
In the drugs of a non-barbiturate type, suppressed respiration, vomiting, nausea and coma can result, and there is a risk of dependency. Therefore, at present, drugs of a benzodian type are in the mainstream in view of safety, but side effects such as antianxiety action, anticonvulsant action and muscle relaxing action are believed to be expressed. It has been also known that “hangover effect” and “amnesia effect” in which sleepiness, swaying, dizziness, fatigue and lassitude remain are strongly expressed, and thus the use of these drugs must be very carefully controlled. Thus, so far there is no excellent compound having a safe and effective normalizing action for infradian rhythm. Furthermore, hypnotics merely induce sleep and have no action of synchronizing to circadian rhythm. For example, when synchronizing to circadian rhythm, it is possible to relieve jet lag, but hypnotics are unable to do that.
As a compound which is able to synchronize to the circadian rhythm, melatonin has been suggested. Melatonin is a hormone which is mostly produced by the pineal gland and its production exhibits a significant change throughout the day. Production at night is as high as 50- to 100-fold that in the daytime.
When the production of melatonin at night is suppressed by administration of a β-blocker, sleeping-waking rhythm disorders, such as deterioration of sleeping, e.g. increase in intermediate awaking at night (Brismar, et al.: Acta Med. Scand., 223, p. 525, 1988) and lowering of awaking level in daytime (Dimenas, et al.: J. Clin. Pharmacol., 30, s103, 1990) may result. As there is a decrease in the secretion of melatonin in older people, supplementing melatonin has been said to be an effective remedy (Garfinkel, et al.: Lancet, 346, p. 541, 1995). Even in very old people where physiological production of melatonin decreases significantly, the amount of melatonin produced is still high in those who are able to have good sleep (Haimov, et al.: Sleep, 18, p. 598, 1995). From these facts, it has been believed that endogenous melatonin is a physiological hypnotic substance participating in adjustment of sleeping-waking rhythm.
There have been many reports on the hypnotic action of endogenous melatonin for the purpose of synchronization of circadian rhythm. However, although there is a report that, as a result of administration of melatonin, good quality sleep, such as shortening of hypnagogic latency time, decrease in midway awaking and improvement of insomnia can be achieved (Zhdanova, et al.: Clin. Pharmacol. Ther., 57, p. 552, 1995), there is also another report that adjusting effect of sleeping and improving affect for sleep disorder are denied (James, et al.: Neuropsychopharmacology, 3, p. 19, 1990).
Non-Patent Document 1
    Brismar, et al.: Acta Med. Scand., 223, p. 525, 1988Non-Patent Document 2    Dimenas, et al.: J. Clin. Pharmacol., 30, s103, 1990Non-Patent Document 3    Garfinkel, et al.: Lancet, 346, p. 541, 1995Non-Patent Document 4    Haimov, et al.: Sleep, 18, p. 598, 1995Non-Patent Document 5    Zhdanova, et al.: Clin. Pharmacol. Ther., 57, p. 552, 1995Non-Patent Document 6    James, et al.: Neuropsuchopharmacology, 3, p. 19, 1990